IGFBP2 is overexpressed by pediatric malignant astrocytomas and induces the repair enzyme DNA-PK.
To identify targets critical to malignant childhood astrocytoma, we compared the expression of receptor tyrosine kinase- associated genes between low-grade and high-grade pediatric astrocytomas. The highest differentially overexpressed gene in high-grade astrocytoma is insulin-like growth factor- binding protein-2 (P = .0006). Immunohistochemistry confirmed overexpression of insulin-like growth factor-binding protein-2 protein (P = .027). Insulin-like growth factor- binding protein-2 stimulation had no effect on astrocytoma cell growth and migration, and minimally inhibited insulin-like growth factor-1-mediated migration, but not insulin-like growth factor-2-mediated migration. However, insulin-like growth factor-binding protein-2 stimulation significantly upregulated the major DNA repair enzyme gene, DNA-PKcs, and induced DNA-dependent protein kinase catalytic subunit protein expression in a time-dependent and dose-dependent manner, whereas insulin-like growth factor-1 had no effect. DNA-PKcs is also highly overexpressed by high-grade astrocytomas. These findings suggest insulin-like growth factor-binding protein-2 plays a role in astrocytoma progression by promoting DNA-damage repair and therapeutic resistance.
Becher
Oren J
OJ
Center for Cancer and Immunology Research, Children's Research Institute, Washington, DC 20010, USA.
Peterson
Katia M
KM
Khatua
Soumen
S
Santi
Maria R
MR
MacDonald
Tobey J
TJ
D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020134:Catalytic Domain / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D051747:DNA-Activated Protein Kinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D014408:Biomarkers, Tumor; D018971:Insulin-Like Growth Factor Binding Protein 2; D009687:Nuclear Proteins; D020794:Receptor Protein-Tyrosine Kinases; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human